The objective of this project is to understand the genetic basis and mechanisms of the immune response and of the failure of response to the major surface antigen of the hepatitis B virus, HBsAg. The extent to which the response is genetically controlled will be defined by immunizing identical twins and their immediate family members and comparing their response with that of MHC-identical siblings. From the study of these and other families and from studies of the response in vitro, the major T cell epitopes of HBsAg will be defined and the response or nonresponse will be correlated with specific major histocompatibility complex (MHC) alleles and fixed, extended haplotypes. The binding of an immunodominant nonapeptide epitope and other T cell epitopes to dendritic cells, monocytes, and B lymphocytes and to isolated class II molecules will be examined and binding will be correlated with the presence or absence of immune response. From the careful study, including sequence determinations in class II genes, of rare responding individuals who are homozygotes for usually nonresponding extended haplotypes or who are MHC identical sibs of nonresponders, we hope to determine whether nucleotide changes affecting the peptide-binding cleft or other parts of class II molecules occur with some frequency and result in response. The relationship between T cell antigen receptor (TCR) Alpha and Vbeta gene and sequence usage and specific MHC alleles and extended haplotypes will be defined in responders and nonresponders to HBsAg. TCR V genes and sequences on T cells proliferating in response to whole HBsAG as well as to individual epitopes will be compared with the overall repertoire of the same responders before boosting and of nonresponders. The results of these studies will be compared with those of Project 2 which explore whether the defect in nonresponders is in antigen presentation or T cell recognition. The effects of possible sequence changes in MHC class II molecules and susceptibility to IgA and other immunoglobulin deficiency (Project 3) will also be examined.
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